Synthesis of 4-alkyl- and 4-(ω-chloroalkyl)-3-hydroxy-5- alkylidenebutenolides based on cyclizations of 4-alkyl- and 4-(ω- chloroalkyl)-1,3-bis(trimethylsilyloxy)buta-1,3-dienes with oxalyl chloride

Article abstract of DOI:10.1055/s-2006-942536

4-Alkyl- and 4-(ω-chloroalkyl)-1,3-bis(trimethylsilyloxy)buta-1,3- dienes were prepared from ethyl acetoacetate in three steps. Their cyclization with oxalyl chloride allowed an efficient synthesis of 4-alkyl- and 4-(ω-chloroalkyl)-5-alkylidenebutenolides. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-942536

PAPER
2865
Synthesis of 4-Alkyl- and 4-(w-Chloroalkyl)-3-hydroxy-5-alkylidenebuten-
olides Based On Cyclizations of 4-Alkyl- and 4-(w-Chloroalkyl)-1,3-bis(tri-
methylsilyloxy)buta-1,3-dienes with Oxalyl Chloride
4
-Alkyl- and 4-(w
-
a
Chloroalky
n
l)-3-hydroxy-5-alk
T
ylidenebutenoli
h
des i Hong Nguyen,a Esen Bellur,a Bettina Appel,a Peter Langer*b,c
a
Institut für Biochemie, Universität Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
b
c
Leibniz Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 10 March 2006; revised 3 May 2006
amide) resulted in decomposition rather than cyclization.
Likewise, the use of ethyl 7-chloro-3-oxoheptanoate
proved to be unsuccessful. Both experiments stand in
sharp contrast to the recent successful application of alkyl
or chloroalkyl-substituted dianions in cyclizations with 1-
bromo-2-chloroethane to give 3-alkyl- or 3-chloroalkyl-2-
alkylidenetetrahydrofurans.6 The failure of the first cy-
clization can be explained by decarbonylation of the
Weinreb amide. Recently, we reported the use of alkyl-
and chloroalkyl-substituted 1,3-bis-silyl enol ethers for
the synthesis of 3-alkyl- and 3-(chloroalkyl)salicylates
and 3-alkyl- and 3-(chloroalkyl)furans.7 Herein, we report
the synthesis of 4-alkyl- and 4-chloroalkyl-3-hydroxy-5-
alkylidenebutenolides by the [3+2] cyclization of alkyl-
and chloroalkyl-substituted 1,3-bis-silyl enol ethers with
oxalyl chloride.
Abstract: 4-Alkyl- and 4-(w-chloroalkyl)-1,3-bis(trimethylsilyl-
oxy)buta-1,3-dienes were prepared from ethyl acetoacetate in three
steps. Their cyclization with oxalyl chloride allowed an efficient
synthesis of 4-alkyl- and 4-(w-chloroalkyl)-5-alkylidenebuten-
olides.
Key words: butenolides, cyclizations, O-heterocycles, silyl enol
ethers
1,3-Bis-silyl enol ethers can be regarded as masked 1,3-
dicarbonyl dianions and represent useful synthetic build-
ing blocks.1,2 Some years ago, we reported the synthesis of
5-alkylidenebutenolides by cyclization of 1,3-dicarbonyl
dianions with the bis Weinreb amide of oxalic acid (dian-
ion methodology)3a and by the cyclization of 1,3-bis-silyl
enol ethers with oxalyl chloride (masked dianion method-
ology).3b–g Recently, we and others reported the applica-
tion of the latter methodology to the synthesis of natural
products, such as pulvinic acids.3e,f,4
Except for commercially available 2a, all b-ketoesters
2b–h were prepared by the reaction of the dianion of ethyl
acetoacetate with alkyl bromides or iodides 1a–g. The b-
ketoesters were transformed, according to a known proce-
dure,2 into the 1,3-bis-silyl enol ethers 4a–h via the mono-
silyl enol ethers 3a–h. The TMSOTf-catalyzed cycliza-
tion of 4a–h with oxalyl chloride afforded the desired 4-
alkyl-5-alkylidenebutenolides 5a–h (Scheme 1, Table 1).
O
O
O
O
OH
OH
HO
multicolic acid
HO
HO
O
A Z-configured exocyclic double bond was observed for
all butenolides 5a–h, due to the steric influence of the
alkyl groups. The configuration was established based on
comparison of the chemical shifts of the proton located at
the exocyclic double bond (5.39–5.44 ppm) with those re-
ported in the literature for related butenolides.3,8
O
HO2C
multicolosic acid
Figure 1 Multicolic and multicolosic acid
The synthesis of butenolides containing a chloro-func-
tionalized alkyl chain was studied next (Scheme 2,
Table 2). The TMSOTf-catalyzed cyclization of oxalyl
chloride with 1,3-bis(trimethylsilyloxy)-7-chlorohepta-
1,3-diene (6a)7 afforded the desired 4-(3-chloropropyl)-5-
alkylidenebutenolide (7a). Starting with 1,3-bis(trimeth-
ylsilyloxy)-10-chlorodeca-1,3-diene (6b),7 the 4-(6-chlo-
rohexyl)-5-alkylidenebutenolide (7b) was prepared.
A number of naturally occurring butenolides, such as mul-
ticolic and multicolosic acid (Figure 1) isolated from Pen-
icillium multicolor, contain a functionalized or non-
functionalized alkyl chain at C-3.5 However, the applica-
tion of our dianion methodology3a to the synthesis of
products containing an alkyl chain located at C-4 of the
butenolide moiety, that is, at a different location, proved
to be unsuccessful. For example, the reaction of dilithiated
ethyl 3-oxodecanoate with oxalic acid bis(Weinreb In summary, we have reported the synthesis of 4-alkyl-
and 4-(w-chloroalkyl)-5-alkylidenebutenolides by cy-
clization of 4-alkyl- and 4-(w-chloroalkyl)-1,3-bis(tri-
methylsilyloxy)buta-1,3-dienes with oxalyl chloride.
SYNTHESIS 2006, No. 17, pp 2865–2872
Advanced online publication: 02.08.2006
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DOI: 10.1055/s-2006-942536; Art ID: T03706SS
© Georg Thieme Verlag Stuttgart · New York

2866
V. T. H. Nguyen et al.
PAPER
O
O
Table 2 Synthesis of 5-Alkylidenebutenolides
O
O
EtO
+
i
R
7
a
b
n
1
4
Yield (%)a
d [ppm] b
EtO
R
X
73
35
5.48
5.41
2a–h
(X = Br, I)
1a–g
ii
a Yields of isolated products.
b Chemical shift (1H NMR, CDCl3) of the proton located at the exo-
cyclic double bond.
Me3SiO
EtO
OSiMe3
R
O
OSiMe3
R
iii
EtO
All solvents were dried by standard methods and all reactions were
1
carried out under an inert atmosphere. For the H and 13C NMR
4a–h
3a–h
spectra the deuterated solvents indicated were used. Mass spectral
data (MS) were obtained by electron ionization (70 eV), chemical
ionization (CI, H2O) or electrospray ionization (ESI). For prepara-
tive scale chromatography silica gel (60–200 mesh) was used. Melt-
ing points are uncorrected.
iv
O
O
O
OH
The syntheses of compounds 2b–h,9–14 3a and 4a,2c and (2Z)-ethyl
EtO
2-[3-ethyl-4-hydroxy-5-oxofuran-2(5H)-ylidene]acetate
(5a)3b
R
have been reported previously.3b
5a–h
b-Ketoesters 2b–h; General Procedure
Scheme 1 Synthesis of 5-alkylidenebutenolides 5a–h. Reagents
and conditions: i: 1) LDA (2.5 equiv), THF, 0 °C, 1 h, 2) 1a–g (1.2
equiv), –78→20 °C; ii: TMSCl, Et3N, benzene, 20 °C, 48 h; iii: 1)
LDA, THF, –78 °C, 1 h, 2) TMSCl, 20 °C, –78→20 °C; iv: TMSOTf
(0.5 equiv), (COCl)2 (1.2 equiv), CH2Cl2, –78→20 °C.
A THF solution of LDA (2.5 equiv) was prepared by the addition of
n-BuLi (15%, hexane) to a solution of i-Pr2NH (2.5 equiv) in THF.
To this solution was added ethyl acetoacetate (1.0 equiv) at 0 °C.
The deep yellow clear solution was stirred at 0 °C for 1 h. To this
solution was added the alkyl halide 1a–g (1.2 equiv) at –78 °C. The
temperature was allowed to rise to ambient temperature over 14 h
and the solution was stirred at r.t. for 2 h. To the solution was added
HCl (10%, 200 mL) and the mixture was extracted with Et2O
(4 × 250 mL). The organic layers were dried over Na2SO4, filtered,
and the filtrate was concentrated in vacuo. The residue was purified
by chromatography (hexane–EtOAc) to give 2b–h.
O
Me3SiO
OSiMe3
OEt
O
O
i
OH
EtO
()n
Cl
Cl
()n
Ethyl 3-Oxoheptanoate (2b)9
6a,b
7a,b
Ethyl acetoacetate (6.30 mL, 50.0 mmol), i-Pr2NH (17.5 mL, 125.0
mmol), n-BuLi (15%, n-hexane; 78.5 mL, 125.0 mmol), and 1-io-
dopropane (1a; 10.20 g, 60.0 mmol) in THF (300 mL) gave 2b after
chromatography (hexane–EtOAc, 100:1→5:1) as a slightly yellow-
ish oil (7.70 g, 93%; 11% enol form).
Scheme 2 Synthesis of 5-alkylidenebutenolides 7a,b. Reagents and
conditions: i: TMSOTf (0.5 equiv), CH2Cl2, –78→20 °C.
Table 1 Synthesis of 5-Alkylidenebutenolides
2–5
a
R
Yield 2 (%)a
Yield 3 (%)a
Yield 4 (%)a
Yield 5 (%)a
db
Et
–
97
89
94
94
98
85
95
94
85
67
75
77
73
74
68
78
76
45
41
39
47
41
40
42
5.44
5.42
5.39
5.42
5.42
5.41
5.42
5.41
b
c
n-Pr
93
n-Bu
n-Hex
n-Hept
n-Oct
n-Non
n-Dec
100
95
d
e
100
96
f
g
100
100
h
a Yields of isolated products.
b Chemical shift (1H NMR, CDCl3) of the proton located at the exocyclic double bond of compound 5.
Synthesis 2006, No. 17, 2865–2872 © Thieme Stuttgart · New York

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4-Alkyl- and 4-(w-Chloroalkyl)-3-hydroxy-5-alkylidenebutenolides
2867
1H NMR (CDCl3, 300 MHz): d = 0.89 (t, J = 7.2 Hz, 3 H, CH3),
1.28 (t, J = 7.2 Hz, 3 H, CH3), 1.33 (sext, J = 7.5 Hz, 2 H, CH2),
1.59 (quint, J = 7.5 Hz, 2 H, CH2), 2.54 (t, J = 7.5 Hz, 2 H, CH2),
3.43 (s, 2 H, CH2), 4.19 (q, J = 7.2 Hz, 2 H, OCH2), 4.98 (s, 1 H,
enol-CH=C), 12.10 (s, 1 H, enol-OH).
1H NMR (CDCl3, 300 MHz): d = 0.87 (t, J = 7.2 Hz, 3 H, CH3),
1.15–1.27 (m, 15 H, CH3, 6 × CH2), 1.56 (quint, J = 7.2 Hz, 2 H,
CH2), 2.51 (t, J = 7.2 Hz, 2 H, CH2), 3.40 (s, 2 H, CH2), 4.14 (q,
J = 7.2 Hz, 2 H, OCH2), 4.96 (s, 1 H, enol-CH=C), 12.12 (s, 1 H,
enol-OH).
13C NMR (CDCl3, 75 MHz): d = 13.1, 13.3 (CH3), 21.8, 22.6, 28.2,
28.5 (2 × CH2), 28.7, 31.1, 41.8, 48.2 (CH2), 60.0 (OCH2), 88.0
(enol-CH=CO), 166.2 (O=CO), 171.8 (enol-O=CO), 178.1 (enol-
OC=CH), 201.4 (C=O).
Ethyl 3-Oxooctanoate (2c)10
Ethyl acetoacetate (19.0 mL, 150.0 mmol), i-Pr2NH (52.7 mL,
375.0 mmol), n-BuLi (15%, n-hexane; 236.0 mL, 375.0 mmol), and
1-bromobutane (1b; 19.4 mL, 180.0 mmol) in THF (300 mL) gave
2c without further purification as a yellowish oil (27.94 g, 100%).
Ethyl 3-Oxotridecanoate (2g)14
IR (neat): 2959 (s), 2933 (s), 2873 (w), 2862 (w), 1744 (s), 1718 (s),
1648 (m), 1622 (m), 1464 (m), 1448 (w), 1414 (m), 1369 (m), 1315
(s), 1261 (s), 1199 (m), 1178 (m), 1155 (m), 1125 (w), 1098 (w),
1030 (m) cm–1.
Ethyl acetoacetate (19.0 mL, 150.0 mmol), i-Pr2NH (52.7 mL,
375.0 mmol), n-BuLi (15%, n-hexane; 236.0 mL, 375.0 mmol), and
1-bromononane (1f; 34.2 mL, 180.0 mmol) in THF (300 mL) gave
2g without further purification as a yellowish oil (38.46 g, 100%).
1H NMR (CDCl3, 300 MHz): d = 0.89 (t, J = 7.2 Hz, 3 H, CH3),
1.25–1.35 (m, 7 H, CH3, 2 × CH2), 1.60 (quint, J = 7.5 Hz, 2 H,
CH2), 2.53 (t, J = 7.5 Hz, 2 H, CH2), 3.43 (s, 2 H, CH2), 4.19 (q,
J = 7.2 Hz, 2 H, OCH2).
IR (neat): 2957 (s), 2927 (s), 2855 (s), 1745 (m), 1716 (m), 1648
(m), 1512 (m), 1463 (m), 1449 (m), 1381 (w), 1351 (w), 1310 (w),
1258 (m), 1232 (m), 1178 (m), 1152 (m), 1122 (m), 1076 (w), 1046
(w) cm–1.
13C NMR (CDCl3, 75 MHz): d = 13.9, 14.1 (CH3), 22.4, 23.2, 31.2,
1H NMR (CDCl3, 300 MHz): d = 0.88 (t, J = 7.2 Hz, 3 H, CH3),
1.23–1.43 (m, 17 H, CH3, 7 × CH2), 1.59 (quint, J = 7.2 Hz, 2 H,
CH2), 2.53 (t, J = 7.2 Hz, 2 H, CH2), 3.44 (s, 2 H, CH2), 4.19 (q,
J = 7.2 Hz, 2 H, OCH2).
13C NMR (CDCl3, 75 MHz): d = 14.1 (2 × CH3), 22.7, 25.6, 27.3,
29.3, 29.5, 29.6, 29.8, 31.3, 31.9, 48.4 (CH2), 61.3 (OCH2), 167.3
(O=CO), 206.6 (C=O).
43.0, 49.3 (CH2), 61.4 (OCH2), 167.3 (O=CO), 203.1 (C=O).
MS (EI, 70 eV): m/z (%) = 186 (M+, 10), 157 (6), 143 (25), 130
(100), 114 (25), 99 (93), 88 (44), 84 (36), 72 (74).
Ethyl 3-Oxodecanoate (2d)11
Ethyl acetoacetate (6.3 mL, 50.0 mmol), i-Pr2NH (17.5 mL, 125.0
mmol), n-BuLi (15%, n-hexane; 78.5 mL, 125.0 mmol), and 1-io-
dohexane (1c; 12.7 g, 60.0 mmol) in THF (300 mL) gave 2d after
chromatography (n-hexane–EtOAc, 100:1→5:1) as a slightly yel-
lowish oil (10.18 g, 95%, enol form 8%).
1H NMR (CDCl3, 300 MHz): d = 0.88 (t, J = 7.2 Hz, 3 H, CH3),
0.84–1.33 (m, 11 H, CH3, 4 × CH2), 1.59 (quint, J = 7.2 Hz, 2 H,
CH2), 2.53 (t, J = 7.2 Hz, 2 H, CH2), 3.43 (s, 2 H, CH2), 4.18 (q,
J = 7.2 Hz, 2 H, OCH2), 4.97 (s, 1 H, enol-CH=C), 12.11 (s, 1 H,
enol-OH).
MS (EI, 70 eV): m/z (%) = 256 (M+, 25), 181 (4), 169 (10), 143 (33),
130 (100), 114 (13), 97 (17), 85 (22).
Ethyl 3-Oxotetradecanoate (2h)14
Ethyl acetoacetate (19.0 mL, 150.0 mmol), i-Pr2NH (52.7 mL,
375.0 mmol), n-BuLi (15%, n-hexane 236.0 mL, 375.0 mmol), and
1-iododecane (1g; 48.27 g, 180.0 mmol) in THF (300 mL) gave 2h
without further purification as a yellowish oil (40.56 g, 100%).
IR (neat): 2957 (m), 2926 (s), 2855 (s), 1745 (s), 1720 (s), 1648 (w),
1630 (w), 1465 (m), 1429 (w), 1369 (w), 1312 (w), 1260 (w), 1233
(m), 1179 (w), 1168 (w), 1152 (w), 1032 (w) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.88 (t, J = 7.2 Hz, 3 H, CH3),
1.26–1.34 (m, 19 H, CH3, 8 × CH2), 1.59 (m, 2 H, CH2), 2.53 (t,
J = 7.5 Hz, 2 H, CH2), 3.43 (s, 2 H, CH2), 4.20 (q, J = 7.2 Hz, 2 H,
OCH2).
13C NMR (CDCl3, 75 MHz): d = 14.1 (2 × CH3), 22.6, 23.5, 29.25,
29.31, 29.40, 29.48, 29.56, 30.5, 31.9, 43.0, 49.3 (CH2), 61.3
(OCH2), 167.3 (O=CO), 203.0 (C=O).
Ethyl 3-Oxoundecanoate (2e)12
Ethyl acetoacetate (19.0 mL, 150.0 mmol), i-Pr2NH (52.7 mL,
375.0 mmol), n-BuLi (15%, n-hexane; 236.0 mL, 375.0 mmol), and
1-iodoheptane (1d; 29.5 mL, 180.0 mmol) in THF (300 mL) gave
2e without further purification as a yellowish oil (34.25 g, 100%).
IR (neat): 2955 (s), 2927 (s), 1747 (s), 1717 (s), 1648 (s), 1632 (s),
1464 (s), 1413 (s), 1370 (s), 1312 (s), 1234 (s), 1175 (s), 1096 (s),
1033 (s), 800 (w) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.85 (t, J = 7.2 Hz, 3 H, CH3),
1.22–1.34 (m, 13 H, CH3, 5 × CH2), 1.59 (quint, J = 7.1 Hz, 2 H,
CH2), 2.54 (t, J = 7.3 Hz, 2 H, CH2), 3.45 (s, 2 H, CH2), 4.19 (q,
J = 7.2 Hz, 2 H, OCH2).
13C NMR (CDCl3, 75 MHz): d = 13.8, 13.9 (CH3), 22.4, 23.2, 28.8,
28.9, 29.1, 31.6, 42.7, 48.9 (CH2), 60.9 (OCH2), 166.9 (O=CO),
202.7 (C=O).
MS (EI, 70 eV): m/z (%) = 270 (M+, 7), 253 (3), 225 (2), 184 (20),
143 (19), 130 (100), 115 (9).
Silyl Enol Ethers 3a–h; General Procedure
To a solution of b-ketoester 2a–h (1.0 equiv) was added Et3N (1.5
equiv). After stirring for 1 h at 20 °C, TMSCl (1.5 equiv) was added
dropwise at 20 °C. After stirring for 48 h, the precipitated salts were
filtered, and the filtrate was concentrated in vacuo to give 3a–h.
Due to the lability of 3a–h, elemental analyses and HRMS data
could not be obtained.
MS (EI, 70 eV): m/z (%) = 228 (M+, 6), 169 (21), 143 (23), 130
(100), 88 (24), 43 (44), 29 (25).
Ethyl 3-Oxododecanoate (2f)13
Ethyl acetoacetate (19.0 mL, 150.0 mmol), i-Pr2NH (52.7 mL,
375.0 mmol), n-BuLi (15%, n-hexane; 236.0 mL, 375.0 mmol), and
1-iodooctane (1e; 32.7 mL, 180.0 mmol) gave 2f after chromatog-
raphy (hexane–EtOAc, 100:1→5:1) as a slightly yellowish oil
(34.90 g, 96%, enol form 12%).
Ethyl 3-(Trimethylsilyloxy)hex-2-enoate (3a)2c
b-Ketoester 2a (12.3 mL, 76.8 mmol), Et3N (17.1 mL, 123.0 mmol),
and TMSCl (17.5 mL, 138.0 mmol) in benzene (150.0 mL) gave 3a
without further purification as a yellowish oil (17.16 g, 97%).
1H NMR (CDCl3, 300 MHz): d = 0.27 [s, 9 H, (CH3)3Si], 0.93 (dt,
J = 7.5, 2.1 Hz, 3 H, CH3), 1.25 (dt, J = 7.2, 1.8 Hz, 3 H, CH3), 1.54
(sext, J = 7.5 Hz, 2 H, CH2), 2.67 (t, J = 7.5 Hz, 2 H, CH2), 4.11 (dq,
J = 7.2, 1.8 Hz, 2 H, OCH2), 5.06, 5.10 (s, 1 H, CH=C).
IR (neat): 2928 (s), 2858 (w), 1743 (s), 1720 (s), 1645 (m), 1457
(m), 1413 (m), 1313 (w), 1255 (m), 1240 (m), 1156 (w), 1095 (w),
1033 (m) cm–1.
Synthesis 2006, No. 17, 2865–2872 © Thieme Stuttgart · New York

2868
V. T. H. Nguyen et al.
PAPER
Ethyl 3-(Trimethylsilyloxy)hept-2-enoate (3b)
MS (EI, 70 eV): m/z (%) = 300 (M+, 3), 271 (26), 215 (48), 202 (36),
187 (100), 130 (53), 74 (87), 43 (47).
b-Ketoester 2b (11.30 g, 65.0 mmol) in benzene (200 mL), Et3N
(9.90 g, 97.0 mmol), and TMSCl (10.60 g, 97.0 mmol) gave 3b
without further purification as a yellowish oil (14.20 g, 89%).
Ethyl 3-(Trimethylsilyloxy)dodec-2-enoate (3f)
b-Ketoester 2f (19.70 g, 81.0 mmol) in benzene (250 mL), Et3N
(12.24 g, 121.0 mmol), and TMSCl (13.15 g, 121.0 mmol) gave 3f
as a yellowish oil (21.60 g, 85%).
1H NMR (CDCl3, 300 MHz): d = 0.21 [s, 9 H, Si(CH3)3], 0.81 (t,
J = 7.2 Hz, 3 H, CH3), 1.10–1.16 (m, 15 H, CH3, 6 × CH2), 1.44 (t,
J = 7.2 Hz, 2 H, CH2), 2.63 (t, J = 7.2 Hz, 2 H, CH2), 4.05 (q, J = 7.2
Hz, 2 H, OCH2), 4.99 (s, 1 H, CH=C).
IR (neat): 2960 (s), 2906 (s), 1716 (s), 1618 (s), 1398 (s), 1208 (s),
1134 (s), 1051 (s), 848 (s), 697 (w) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.24 [s, 9 H, (CH3)3Si], 0.86 (t,
J = 7.2 Hz, 3 H, CH3), 1.15–1.21 (m, 5 H, CH3, CH2), 1.31 (quint,
J = 7.1 Hz, 1 H, CH2), 1.46 (quint, J = 7.0 Hz, 1 H, CH2), 2.62 (t,
J = 7.2 Hz, 1 H, CH2), 2.63 (t, J = 7.2 Hz, 1 H, CH2), 4.04 (q, J = 7.2
Hz, 2 H, OCH2), 5.03 (s, 1 H, CH=C).
13C NMR (CDCl3, 75 MHz): d = 0.5 [3 C, Si(CH3)3], 13.8, 14.3
(CH3), 22.3, 26.5, 31.3, 32.9 (CH2), 59.0 (OCH2), 99.4 (CH=C),
167.2 (O=CO), 173.3 (OC=CH).
13C NMR (CDCl3, 75 MHz): d = 0.3 [3 C, Si(CH3)3], 13.8, 14.1
(CH3), 22.4, 26.8, 29.0, 29.1, 29.2, 31.7, 32.9, 37.9 (CH2), 58.8
(OCH2), 98.6 (CH=C), 167.9 (O=CO), 172.7 (OC=CH).
MS (EI, 70 eV): m/z (%) = 244 (M+, 4), 202 (31), 187 (54), 74 (68),
28 (100).
Ethyl 3-(Trimethylsilyloxy)tridec-2-enoate (3g)
b-Ketoester 2g (38.46 g, 150.0 mmol), Et3N (31.20 mL, 225.0
mmol), and TMSCl (28.40 mL, 225.0 mmol) in benzene (150 mL)
gave 3g without further purification as a brownish oil (47.00 g,
95%).
Ethyl 3-(Trimethylsilyloxy)oct-2-enoate (3c)
b-Ketoester 2c (27.94 g, 150.0 mmol), Et3N (31.2 mL, 225.0
mmol), and TMSCl (28.40 mL, 225.0 mmol) in benzene (150 mL)
gave 3c without further purification as a brownish oil (36.35 g,
94%).
1H NMR (CDCl3, 300 MHz): d = 0.27 [s, 9 H, Si(CH3)3], 0.89 (t,
J = 7.2 Hz, 3 H, CH3), 1.26 (t, J = 7.2 Hz, 3 H, CH3), 1.27–1.37 (m,
4 H, 2 × CH2), 1.52 (quint, J = 7.2 Hz, 2 H, CH2), 2.69 (t, J = 7.2
Hz, 2 H, CH2), 4.12 (q, J = 7.2 Hz, 2 H, OCH2), 5.06 (s, 1 H,
CH=C).
IR (neat): 2957 (s), 2927 (s), 2855 (s), 1747 (s), 1717 (s), 1463 (s),
1309 (m), 1233 (s), 1136 (s), 1049 (s), 849 (s), 755 (w) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.24 [s, 9 H, Si(CH3)3], 0.86 (t,
J = 7.2 Hz, 3 H, CH3), 1.19–1.31 (m, 17 H, CH3, 7 × CH2), 1.45 (t,
J = 7.2 Hz, 2 H, CH2), 2.66 (t, J = 7.2 Hz, 2 H, CH2), 4.11 (t, J = 7.2
Hz, 2 H, OCH2), 5.02 (s, 1 H, CH=C).
13C NMR (CDCl3, 75 MHz): d = 0.5 [3 C, Si(CH3)3], 13.9, 14.3
(CH3), 23.3, 26.9, 28.9, 29.2, 29.4, 31.8, 33.1, 42.9, 49.2 (CH2),
59.1 (OCH2), 98.8 (CH=C), 167.5 (O=CO), 173.3 (OC=CH).
13C NMR (CDCl3, 75 MHz): d = 0.5 [3 C, Si(CH3)3], 13.8, 14.3
(CH3), 22.3, 26.5, 31.3, 33.0 (CH2), 59.0 (OCH2), 98.7 (CH=C),
167.4 (O=CO), 173.3 (OC=CH).
Ethyl 3-(Trimethylsilyloxy)tetradec-2-enoate (3h)
b-Ketoester 2h (40.56 g, 150.0 mmol), Et3N (31.20 mL, 225.0
mmol), and TMSCl (28.40 mL, 225.0 mmol) in benzene (150 mL)
gave 3h without further purification as a brownish oil (48.28 g,
94%).
Ethyl 3-(Trimethylsilyloxy)dec-2-enoate (3d)
b-Ketoester 2d (2.00 g, 9.3 mmol), Et3N (2.07 mL, 14.9 mmol), and
TMSCl (2.12 mL, 16.8 mmol) in benzene (40 mL) gave 3d without
further purification as a yellowish oil (2.52 g, 94%).
IR (neat): 2957 (s), 2927 (s), 2855 (s), 2855 (s), 1715 (s), 1619 (s),
1463 (s), 1374 (s), 1306 (s), 1256 (s), 1209 (s), 1135 (s), 1051 (s),
849 (s), 758 (m) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.27 [s, 9 H, Si(CH3)3], 0.89 (t,
J = 7.2 Hz, 3 H, CH3), 1.24–1.37 (m, 17 H, CH3, 7 × CH2), 1.52
(quint, J = 7.2 Hz, 2 H, CH2), 2.09 (t, J = 7.2 Hz, 2 H, CH2), 4.18 (q,
J = 7.2 Hz, 2 H, OCH2), 5.11 (s, 1 H, CH=C).
IR (neat): 2959 (s), 2930 (s), 2858 (s), 1715 (s), 1620 (s), 1375 (m),
1256 (s), 1136 (s), 1051 (s), 840 (s), 678 (m) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.21 [s, 9 H, Si(CH3)3], 0.88 (t,
J = 7.2 Hz, 3 H, CH3), 1.16–1.27 (m, 11 H, CH3, 4 × CH2), 1.51
(quint, J = 7.2 Hz, 2 H, CH2), 2.68 (t, J = 7.2 Hz, 2 H, CH2), 4.11 (q,
J = 7.2 Hz, 2 H, OCH2), 5.05 (s, 1 H, CH=C).
13C NMR (CDCl3, 75 MHz): d = 0.1 [3 C, Si(CH3)3], 14.1, 14.4
(CH3), 22.6, 27.0, 29.1, 31.6, 31.8, 33.2 (CH2), 59.2 (OCH2), 98.8
(CH=C), 167.6 (O=CO), 173.5 (OC=CH).
1,3-Bis-silyl Enol Ethers 4a–h; General Procedure
A solution of LDA was prepared by the addition of n-BuLi (1.6 M
solution, hexanes; 1.5 equiv) to a solution of i-Pr2NH (1.5 equiv) in
THF at 0 °C and the resulting solution was stirred for 20 min. A so-
lution of 3a–h (1.0 equiv) in THF was added at –78 °C, stirred for
1 h at –78 °C, and then TMSCl (1.5 equiv) was added. The temper-
ature of the solution was allowed to rise to ambient temperature
over 2 h and the solution was stirred for 1 h at 20 °C. The solvent
was removed in vacuo and n-hexane was added to the residue. The
precipitated LiCl was removed by filtration under inert conditions
and the filtrate was concentrated in vacuo to give 4a–h. The product
was stored at –20 °C and used without further purification. Due to
the lability of 4a–h, elemental analyses and HRMS data could not
be obtained.
MS (EI, 70 eV): m/z (%) = 286 (M+, 15), 271 (26), 215 (34), 202
(36), 187 (84), 74 (100), 29 (26).
Ethyl 3-(Trimethylsilyloxy)undec-2-enoate (3e)
b-Ketoester 2e (34.25 g, 150.0 mmol), Et3N (31.2 mL, 225.0
mmol), and TMSCl (28.4 mL, 225.0 mmol) in benzene (150 mL)
gave 3e without further purification as a brownish oil (44.14 g,
98%).
IR (neat): 2958 (s), 2929 (s), 1743 (s), 1715 (s), 1463 (s), 1311 (m),
1255 (s), 1142 (s), 1015 (s), 848 (m), 735 (s) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.26 [s, 9 H, Si(CH3)3], 0.88 (t,
J = 7.2 Hz, 3 H, CH3), 1.20–1.27 (m, 13 H, CH3, 5 × CH2), 1.48
(quint, J = 7.2 Hz, 2 H, CH2), 2.69 (t, J = 7.2 Hz, 2 H, CH2), 4.18 (q,
J = 7.2 Hz, 2 H, OCH2), 5.11 (s, 1 H, CH=C).
13C NMR (CDCl3, 75 MHz): d = 0.4 [3 C, Si(CH3)3], 13.8, 14.2
(CH3), 22.5, 26.8, 28.9, 29.0, 29.2, 31.6, 32.9 (CH2), 58.9 (OCH2),
98.7 (CH=C), 167.2 (O=CO), 173.1 (OC=CH).
1-Ethoxy-1,3-bis(trimethylsilyloxy)hexa-1,3-diene (4a)2c
Silyl enol ether 3a (16.13 g, 70.0 mmol), i-Pr2NH (14.80 mL, 105.0
mmol), n-BuLi (2.5 M, n-hexane; 42.00 mL, 105.0 mmol), and
TMSCl (13.30 mL, 105.0 mmol) in THF (140 mL) gave 4a without
further purification as a brownish oil (18.00 g, 85%).
Synthesis 2006, No. 17, 2865–2872 © Thieme Stuttgart · New York

PAPER
4-Alkyl- and 4-(w-Chloroalkyl)-3-hydroxy-5-alkylidenebutenolides
2869
1H NMR (CDCl3, 300 MHz): d = 0.16 [s, 9 H, Si(CH3)3], 0.24 [s, 9
H, Si(CH3)3], 0.94 (t, J = 7.5 Hz, 3 H, CH3), 1.30 (t, J = 7.1 Hz, 3 H,
CH3), 2.08 (quint, J = 7.4 Hz, 2 H, CH2), 3.73 (q, J = 7.1 Hz, 2 H,
OCH2), 3.86 (s, 1 H, CH=C), 4.86 (t, J = 7.1 Hz, 1 H, CH=C).
IR (neat): 2958 (s), 2927 (s), 2856 (s), 1724 (s), 1650 (s), 1463 (s),
1253 (s), 1154 (s), 1041 (s), 846 (s) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.18 [s, 9 H, Si(CH3)3], 0.24 [s, 9
H, Si(CH3)3], 0.88 (t, J = 7.2 Hz, 3 H, CH3), 1.22–1.33 (m, 13 H,
CH3, 5 × CH2), 2.05 (q, J = 7.1 Hz, 2 H, CH2), 3.74 (q, J = 7.2 Hz,
2 H, OCH2), 3.86 (s, 1 H, CH=C), 4.88 (t, J = 7.2 Hz, 1 H, CH=C).
13C NMR (CDCl3, 75 MHz): d = 0.5 (3 C), 1.8 [3 C, Si(CH3)3], 14.1,
14.3 (CH3), 22.7, 25.7, 29.2, 29.3, 29.9, 31.9 (CH2), 63.2 (OCH2),
78.3, 108.6 (CH=C), 144.4, 156.0 (C).
1-Ethoxy-1,3-bis(trimethylsilyloxy)hepta-1,3-diene (4b)
Silyl enol ether 3b (13.30 g, 55.0 mmol), i-Pr2NH (8.30 g, 81.0
mmol), n-BuLi (50.63 mL, 81.0 mmol), and TMSCl (8.80 g, 81.0
mmol) in THF (200 mL) gave 4b as a brownish oil (11.70 g, 67%).
IR (neat): 2960 (s), 2903 (s), 1740 (s), 1654 (s), 1460 (m), 1373 (s),
1254 (s), 1179 (s), 1077 (s), 844 (s), 757 (s) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.20 [s, 9 H, Si(CH3)3], 0.25 [s, 9
H, Si(CH3)3], 0.91 (t, J = 7.2 Hz, 3 H, CH3), 1.25–1.37 (m, 5 H,
CH3, CH2), 2.04 (q, J = 7.3 Hz, 2 H, CH2), 3.75 (q, J = 7.2 Hz, 2 H,
OCH2), 3.86 (s, 1 H, CH=C), 4.89 (t, J = 7.1 Hz, 1 H, CH=C).
13C NMR (CDCl3, 75 MHz): d = 0.5 (3 C), 1.3 [3 C, Si(CH3)3], 13.4,
13.9 (CH3), 25.1, 27.6 (CH2), 67.3 (OCH2), 78.0, 107.8 (CH=C),
144.1, 155.5 (C).
MS (EI, 70 eV): m/z (%) = 372 (M+, 6), 371 (22), 286 (30), 214.4
(23), 168.5 (66), 73.5 (100), 28 (49).
1-Ethoxy-1,3-bis(trimethylsilyloxy)dodeca-1,3-diene (4f)
Silyl enol ether 3f (20.40 g, 65.0 mmol), i-Pr2NH (9.80 g, 97.0
mmol), n-BuLi (60.63 mL, 97.0 mmol), and TMSCl (10.54 g, 97.0
mmol) in THF (200 mL) gave 4f without further purification as a
brownish oil (18.54 g, 74%).
IR (neat): 2959 (s), 2926 (s), 2855 (s), 1719 (s), 1655 (s), 1463 (s),
1253 (s), 1078 (s), 842 (s), 757 (s) cm–1.
MS (EI, 70 eV): m/z (%) = 316 (M+, 18), 287 (25), 259 (13), 169
(95), 147 (24), 74 (100), 28 (18).
1H NMR (CDCl3, 300 MHz): d = 0.16 [s, 9 H, Si(CH3)3], 0.25 [s, 9
H, Si(CH3)3], 0.87 (t, J = 7.2 Hz, 3 H, CH3), 1.24–1.41 (m, 15 H,
CH3, 6 × CH2), 2.05 (q, J = 7.1 Hz, 2 H, CH2), 3.75 (q, J = 7.2 Hz,
2 H, OCH2), 3.87 (s, 1 H, CH=C), 4.89 (t, J = 7.1 Hz, 1 H, CH=C).
13C NMR (CDCl3, 75 MHz): d = 0.8 (3 C), 1.8 [3 C, Si(CH3)3], 14.0,
14.3 (CH3), 22.7, 25.7, 29.0, 29.3, 29.5, 31.9, 33.1 (CH2), 63.1
(OCH2), 78.4, 108.6 (CH=C), 144.4, 156.0 (C).
1-Ethoxy-1,3-bis(trimethylsilyloxy)octa-1,3-diene (4c)
Silyl enol ether 3c (24.70 g, 95.0 mmol), i-Pr2NH (14.42 g, 142.5
mmol), n-BuLi (89.10 mL, 142.5 mmol), and TMSCl (15.50 g,
142.5 mmol) in THF (150 mL) gave 4c without further purification
as a brownish oil (23.36 g, 75%).
IR (neat): 2959 (s), 2934 (s), 2869 (s), 1745 (s), 1718 (s), 1646 (s),
1463 (s), 1415 (s), 1255 (s), 1155 (s), 1035 (s), 844 (s), 756 (w)
cm–1.
MS (EI, 70 eV): m/z (%) = 386 (M+, 11), 331 (15), 287 (17), 169
(42), 147 (40), 74 (100), 29.1 (9).
1H NMR (CDCl3, 300 MHz): d = 0.18 [s, 9 H, Si(CH3)3], 0.23 [s, 9
H, Si(CH3)3], 0.87 (t, J = 7.2 Hz, 3 H, CH3), 1.25–1.34 (m, 7 H,
CH3, 2 × CH2), 2.07 (q, J = 7.1 Hz, 2 H, CH2), 3.73 (q, J = 7.2 Hz,
2 H, OCH2), 3.85 (s, 1 H, CH=C), 4.87 (t, J = 7.1 Hz, 1 H, CH=C).
13C NMR (CDCl3, 75 MHz): d = 0.43 (3 C), 1.8 [3 C, Si(CH3)3],
14.1, 14.3 (CH3), 22.6, 25.6, 32.3 (CH2), 63.1 (OCH2), 78.3, 108.5
(CH=C), 144.4, 156.0 (C).
1-Ethoxy-1,3-bis(trimethylsilyloxy)trideca-1,3-diene (4g)
Silyl enol ether 3g (26.30 g, 80.0 mmol), i-Pr2NH (12.14 g, 120.0
mmol), n-BuLi (75.00 mL, 120.0 mmol), and TMSCl (13.04 g,
120.0 mmol) in THF (200 mL) gave 4g without further purification
as a brownish oil (21.60 g, 68%).
IR (neat): 2959 (s), 2927 (s), 2856 (s), 1743 (s), 1655 (s), 1463 (s),
1254 (s), 1053 (s), 846 (s), 757 (m) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.18 [s, 9 H, Si(CH3)3], 0.27 [s, 9
H, Si(CH3)3], 0.89 (t, J = 7.2 Hz, 3 H, CH3), 1.23–1.34 (m, 17 H,
CH3, 7 × CH2), 2.05 (q, J = 7.1 Hz, 2 H, CH2), 3.75 (q, J = 7.2 Hz,
2 H, OCH2), 4.19 (s, 1 H, CH=C), 4.89 (t, J = 7.2 Hz, 1 H, CH=C).
13C NMR (CDCl3, 75 MHz): d = 0.5 (3 C), 1.9 [3 C, Si(CH3)3], 14.1,
14.4 (CH3), 22.7, 25.8, 29.4, 29.5, 29.7, 30.2, 31.9, 33.1 (CH2), 63.1
(OCH2), 78.4, 108.6 (CH=C), 144.3, 155.9 (C).
MS (EI, 70 eV): m/z (%) = 330 (M+, 20), 287 (28), 259 (12), 169
(97), 146 (24), 74 (100), 28 (16).
1-Ethoxy-1,3-bis(trimethylsilyloxy)deca-1,3-diene (4d)
Silyl enol ether 3d (14.31 g, 50.0 mmol), i-Pr2NH (7.60 g, 75.0
mmol), n-BuLi (46.90 mL, 75.0 mmol), and TMSCl (8.15 g, 75.0
mmol) in THF (150 mL) gave 4d without further purification as a
brownish oil (13.80 g, 77%).
MS (EI, 70 eV): m/z (%) = 400 (M+, 4), 330 (5), 290 (30), 186 (20),
168.5 (41), 146 (29), 73 (100), 43 (41), 28 (34).
IR (neat): 2959 (s), 2930 (s), 2858 (s), 1715 (s), 1620 (s), 1462 (s),
1375 (s), 1256 (s), 1110 (s), 849 (s), 678 (s) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.17 [s, 9 H, Si(CH3)3], 0.24 [s, 9
H, Si(CH3)3], 0.89 (t, J = 7.2 Hz, 3 H, CH3), 1.31–1.42 (m, 11 H,
CH3, 4 × CH2), 2.07 (q, J = 7.0 Hz, 2 H, CH2), 3.74 (q, J = 7.2 Hz,
2 H, OCH2), 3.86 (s, 1 H, CH=C), 4.90 (t, J = 7.2 Hz, 1 H, CH=C).
13C NMR (CDCl3, 75 MHz): d = 0.5 (3 C), 1.9 [3 C, Si(CH3)3], 14.1,
14.3 (CH3), 22.7, 25.7, 29.0, 30.1, 31.9 (CH2), 63.1 (OCH2), 78.3,
108.6 (CH=C), 144.3, 156.9 (C).
1-Ethoxy-1,3-bis(trimethylsilyloxy)tetradeca-1,3-diene (4h)
Silyl enol ether 3h (20.50 g, 60.0 mmol), i-Pr2NH (9.11 g, 90.0
mmol), n-BuLi (56.30 mL, 90.0 mmol), and TMSCl (9.80 g, 90.0
mmol) in THF (150 mL) gave 4h as a brownish oil (19.50 g, 78%).
IR (neat): 2958 (s), 2928 (s), 2855 (s), 1717 (s), 1653 (s), 1463 (s),
1253 (s), 1135 (s), 1019 (s), 855 (s), 7576.2 (m) cm–1
.
1H NMR (CDCl3, 300 MHz): d = 0.18 [s, 9 H, Si(CH3)3], 0.24 [s, 9
H, Si(CH3)3], 0.89 (t, J = 7.2 Hz, 3 H, CH3), 1.22–1.34 (m, 19 H,
CH3, 8 × CH2), 2.07 (t, J = 7.1 Hz, 2 H, CH2), 3.75 (q, J = 7.1 Hz, 2
H, OCH2), 3.87 (s, 1 H, CH=C), 4.88 (t, J = 7.2 Hz, 1 H, CH=C).
13C NMR (CDCl3, 75 MHz): d = 0.5 (3 C), 1.8 [3 C, Si(CH3)3], 14.1,
14.4 (CH3), 22.7, 23.2, 25.7, 29.4, 29.5, 29.7, 29.7, 30.2, 31.9
(CH2), 63.2 (OCH2), 78.4, 108.6 (CH=C), 144.3, 156.0 (CO).
MS (EI, 70 eV): m/z (%) = 358 (M+, 29), 343 (9), 287 (38), 259 (16),
243 (15), 169 (95), 146.5 (16), 74 (100), 28 (43).
1-Ethoxy-1,3-bis(trimethylsilyloxy)undeca-1,3-diene (4e)
Silyl enol ether 3e (17.00 g, 56.0 mmol), i-Pr2NH (8.50 g, 84.0
mmol), n-BuLi (52.50 mL, 84.0 mmol), and TMSCl (9.10 g, 84.0
mmol) in THF (150 mL) gave 4e without further purification as a
brownish oil (15.26 g, 73%).
MS (EI, 70 eV): m/z (%) = 414.6 (M+, 22), 326 (11), 286 (39), 186
(26), 168 (71), 146 (21), 73 (100), 28 (21).
Synthesis 2006, No. 17, 2865–2872 © Thieme Stuttgart · New York

2870
V. T. H. Nguyen et al.
PAPER
Butenolides 5a–h, 7a, and 7b; General Procedure
IR (neat): 3458 (br), 2930 (m), 1791 (m), 1698 (m), 1644 (s), 1136
(m) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.89 (t, J = 6.8 Hz, 3 H, CH3),
1.22–1.37 (m, 9 H, CH3, 3 × CH2), 1.55 (quint, J = 7.0 Hz, 2 H,
CH2), 2.38 (t, J = 7.5 Hz, 2 H, CH2), 4.26 (q, J = 7.1 Hz, 2 H,
OCH2), 5.42 (s, 1 H, CH).
13C NMR (CDCl3, 75 MHz): d = 14.0, 14.2 (CH3), 22.4, 22.5, 27.8,
29.0, 31.4 (CH2), 60.9 (OCH2), 96.8 (CH), 125.3, 142.7, 156.9,
163.7, 164.9 (C).
To a solution of TMSOTf (0.5 equiv) in CH2Cl2 was added a solu-
tion of 4a–h, 6a, or 6b (1.0 equiv) in CH2Cl2 at –78 °C. Subsequent-
ly, (ClCO)2 (1.2 equiv) was added at –78 °C. The temperature of the
solution was allowed to rise to 20 °C over 12 h. A sat. solution of
brine–10% HCl (4:1) was added. The organic layer was separated
and the aqueous layer was repeatedly extracted with CH2Cl2. The
combined organic layers were dried (Na2SO4) and filtered. The fil-
trate was concentrated in vacuo and the residue was purified by col-
umn chromatography (silica gel; n-hexane–EtOAc).
MS (EI, 70 eV): m/z (%) = 268 (M+, 33), 241 (24), 223 (33), 194
(66), 166 (21), 151 (51), 127 (34), 109 (26), 70 (60), 55 (69), 43
(100), 29 (97).
(2Z)-Ethyl 2-[4-Hydroxy-5-oxo-3-propylfuran-2(5H)-
ylidene]acetate (5b)
1,3-Bis-silyl enol ether 4b (0.500 g, 1.58 mmol), (COCl)2 (0.241 g,
1.90 mmol), and TMSOTf (0.176 g, 0.79 mmol) in CH2Cl2 (30 mL)
gave 5b after chromatography (n-hexane–EtOAc, 5:1) as a yellow-
ish solid (0.161 g, 45%).
UV-Vis (MeCN, nm): lmax (log e) = 218 (3.70), 248 (3.76), 298
(3.95), 401 (3.47).
Anal. Calcd for C14H20O5 (268.306): C, 62.67; H, 7.51. Found: C,
62.91; H, 7.97.
IR (KBr): 3421 (br), 2963 (w), 1792 (m), 1643 (m), 1136 (w), 1136
(m), 1035 (w) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.98 (t, J = 7.3 Hz, 3 H, CH3),
1.29 (t, J = 7.2 Hz, 3 H, CH3), 1.61–1.65 (m, J = 7.5 Hz, 2 H, CH2),
2.37 (t, J = 7.5 Hz, 2 H, CH2), 4.27 (q, J = 7.1 Hz, 2 H, OCH2), 5.42
(s, 1 H, CH).
13C NMR (CDCl3, 75 MHz): d = 13.9, 14.2 (CH3), 21.2, 24.4 (CH2),
60.91 (OCH2), 97.0 (CH), 125.0, 142.7, 156.8, 163.6, 164.9 (C).
MS (EI, 70 eV): m/z (%) = 227 ([M + 1]+, 9), 226 (M+, 69), 198
(23), 181 (72), 180 (70), 151 (96), 127 (37), 110 (67), 70 (83), 55
(49), 43 (88), 29 (100).
(2Z)-Ethyl 2-[3-Heptyl-4-hydroxy-5-oxofuran-2(5H)-
ylidene]acetate (5e)
1,3-Bis-silyl enol ether 4e (0.455 g, 1.22 mmol), (COCl)2 (0.186 g,
1.47 mmol), and TMSOTf (0.136 g, 0.61 mmol) in CH2Cl2 (30 mL)
gave 5e after chromatography (n-hexane–EtOAc, 5:1) as a yellow-
ish oil (0.162 g, 47%).
IR (neat): 3451 (br), 2957 (m), 1793 (m), 1701 (m), 1644 (s), 1135
(m) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.89 (t, J = 6.8 Hz, 3 H, CH3),
1.29 (m, 8 H, 4 × CH2), 1.38 (t, J = 7.2 Hz, 3 H, CH3), 1.59 (m, 2 H,
CH2), 2.38 (t, J = 7.2 Hz, 2 H, CH2), 4.26 (q, J = 7.2 Hz, 2 H,
OCH2), 5.42 (s, 1 H, CH).
UV-Vis (MeCN, nm): lmax (log e) = 218 (3.72), 248 (3.77), 298
(4.03), 400 (3.52).
13C NMR (CDCl3, 75 MHz): d = 14.0, 14.2 (CH3), 22.5, 22.6, 27.8,
28.9, 29.3, 31.7 (CH2), 60.9 (OCH2), 96.9 (CH), 125.3, 142.7,
156.8, 163.7, 164.9 (C).
Anal. Calcd for C11H14O5 (226.226): C, 58.40; H, 6.23. Found: C,
58.30; H, 6.73.
MS (EI, 70 eV): m/z (%) = 283 ([M + 1]+, 4), 282 (M+, 30), 255
(10), 237 (36), 212 (25), 167 (29), 151 (53), 109 (32), 70 (54), 55
(63), 43 (79), 29 (100).
(2Z)-Ethyl 2-[3-Butyl-4-hydroxy-5-oxofuran-2(5H)-yl-
idene]acetate (5c)3b
1,3-Bis-silyl enol ether 4c (0.500 g, 1.51 mmol), (COCl)2 (0.231 g,
1.82 mmol), and TMSOTf (0.168 g, 0.76 mmol) in CH2Cl2 (30 mL)
gave 5c after chromatography (n-hexane–EtOAc, 5:1) as a yellow-
ish oil (0.149 g, 41%).
UV-Vis (MeCN, nm): lmax (log e) = 218 (3.72), 249 (3.71), 298
(3.99), 401 (3.37).
IR (neat): 3558 (m), 3440 (br), 2978 (m), 2934 (m), 2966 (m), 1745
(m), 1646 (m), 1124 (s) cm–1.
(2Z)-Ethyl 2-[4-Hydroxy-3-octyl-5-oxofuran-2(5H)-yl-
idene]acetate (5f)
1H NMR (CDCl3, 300 MHz): d = 0.94 (t, J = 7.2 Hz, 3 H, CH3),
1.28–1.40 (m, 2 H, CH2), 1.38 (t, J = 7.2 Hz, 3 H, CH3), 1.56 (quint,
J = 7.2 Hz, 2 H, CH2), 2.38 (t, J = 7.2 Hz, 2 H, CH2), 4.27 (q, J = 7.2
Hz, 2 H, OCH2), 5.39 (s, 1 H, CH).
1,3-Bis-silyl enol ether 4f (0.500 g, 1.29 mmol), (COCl)2 (0.197 g,
1.55 mmol), and TMSOTf (0.144 g, 0.65 mmol) in CH2Cl2 (30 mL)
gave 5f after chromatography (n-hexane–EtOAc, 5:1) as a yellow-
ish oil (0.160 g, 41%).
13C NMR (CDCl3, 75 MHz): d = 13.7, 14.2 (CH3), 22.1, 22.5, 29.9
(CH2), 60.8 (OCH2), 96.4 (CH), 125.0, 143.2, 157.2, 163.8, 164.9
(C).
MS (EI, 70 eV): m/z (%) = 240 (M+, 37), 213 (42), 195 (26), 171
(39), 166 (44), 125 (69), 114 (37), 86 (44), 55 (59), 43 (76), 29
(100).
IR (neat): 3583 (m), 3452 (br), 2928 (m), 1794 (m), 1705 (m), 1644
(m), 1135 (m), 1036 (m) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.88 (t, J = 6.7 Hz, 3 H, CH3),
1.27 (m, 10 H, 5 × CH2), 1.37 (t, J = 7.2 Hz, 3 H, CH3), 1.58 (t,
J = 7.5 Hz, 2 H, CH2), 2.37 (t, J = 7.5 Hz, 2 H, CH2), 4.26 (q, J = 7.1
Hz, 2 H, OCH2), 5.41 (s, 1 H, CH).
13C NMR (CDCl3, 75 MHz): d = 14.1, 14.2 (CH3), 22.5, 22.6, 27.8,
29.1, 29.2, 29.4, 31.8 (CH2), 60.9 (OCH2), 97.1 (CH), 125.3, 142.5,
156.7, 163.6, 164.5 (C).
UV-Vis (MeCN, nm): lmax (log e) = 221 (3.59), 241 (3.61), 298
(3.66), 400 (3.95).
MS (EI, 70 eV): m/z (%) = 296 (M+, 11), 269 (16), 251 (10), 222
(11), 181 (11), 155 (17), 130 (57), 114 (21), 85 (20), 70 (36), 55
(48), 43 (86), 28 (100).
(2Z)-Ethyl 2-[3-Hexyl-4-hydroxy-5-oxofuran-2(5H)-yl-
idene]acetate (5d)
1,3-Bis-silyl enol ether 4d (0.500 g, 1.40 mmol), (COCl)2 (0.213 g,
1.67 mmol), and TMSOTf (0.155 g, 0.70 mmol) in CH2Cl2 (30 mL)
gave 5d after chromatography (n-hexane–EtOAc, 5:1) as a yellow-
ish oil (0.146 g, 39%).
UV-Vis (MeCN, nm): lmax (log e) = 240 (3.55), 298 (3.58), 401
(2.85).
Anal. Calcd for C16H24O5 (296.359): C, 64.85; H, 8.17. Found: C,
65.43; H, 8.89.
Synthesis 2006, No. 17, 2865–2872 © Thieme Stuttgart · New York

PAPER
4-Alkyl- and 4-(w-Chloroalkyl)-3-hydroxy-5-alkylidenebutenolides
UV-Vis (MeCN, nm): lmax (log e) = 216 (3.92), 298 (4.10).
2871
(2Z)-Ethyl 2-[4-Hydroxy-3-nonyl-5-oxofuran-2(5H)-yl-
idene]acetate (5g)
1,3-Bis-silyl enol ether 4g (0.500 g, 1.25 mmol), (COCl)2 (0.190 g,
1.50 mmol), and TMSOTf (0.139 g, 0.62 mmol) in CH2Cl2 (30 mL)
gave 5g after chromatography (n-hexane–EtOAc, 5:1) as a yellow-
ish oil (0.149 g, 40%).
HRMS (ESI): m/z calcd for C11H1335ClO5 ([M + 1]+): 261.05298;
found: 261.05257.
(2Z)-Ethyl 2-[3-(6-Chlorohexyl)-4-hydroxy-5-oxofuran-2-(5H)-
ylidene]acetate (7b)
IR (neat): 3438 (br), 2927 (m), 1794 (m), 1643 (s), 1325 (m), 1135
(m) cm–1.
1H NMR (CDCl3, 300 MHz): d = 0.89 (t, J = 6.7 Hz, 3 H, CH3),
1.29 (m, 12 H, 6 × CH2), 1.33 (t, J = 7.1 Hz, 3 H, CH3), 1.59 (m,
J = 7.0 Hz, 2 H, CH2), 2.38 (t, J = 7.4 Hz, 2 H, CH2), 4.25 (q, J = 7.1
Hz, 2 H, OCH2), 5.42 (s, 1 H, CH).
Compound 6b (1.180 g, 3.00 mmol), (COCl)2 (0.457 g, 6.00 mmol),
and TMSOTf (0.333 g, 1.50 mmol) in CH2Cl2 (60 mL) gave 7b after
chromatography (n-hexane–EtOAc, 5:1) as a yellowish solid (0.315
g, 35%).
IR (KBr): 3427 (m), 2933 (s), 1789 (m), 1651 (m), 1304 (m), 1145
(m) cm–1.
13C NMR (CDCl3, 75 MHz): d = 14.1, 14.2 (CH3), 22.5, 22.6, 27.8
(CH2), 29.2, 29.4 (2 × CH2), 31.8 (CH2), 60.9 (OCH2), 96.9 (CH),
125.3, 142.6, 156.8, 163.7, 164.9 (C).
MS (EI, 70 eV): m/z (%) = 310 (M+, 34), 283 (14), 265 (33), 236
(34), 212 (41), 198 (23), 151 (42), 130 (42), 109 (27), 70 (52), 55
(61), 43 (100), 29 (75).
1H NMR (CDCl3, 300 MHz): d = 1.32 (t, J = 7.1 Hz, 3 H, CH3),
1.39 (m, J = 7.2 Hz, 2 H, CH2), 1.46 (m, J = 6.9, 2.0 Hz, 2 H, CH2),
1.59 (quint, J = 7.5 Hz, 2 H, CH2), 1.78 (quint, J = 6.8 Hz, 2 H,
CH2), 2.39 (t, J = 7.5 Hz, 2 H, CH2), 3.54 (t, J = 6.6 Hz, 2 H, CH2),
4.27 (q, J = 7.1 Hz, 2 H, OCH2), 5.41 (s, 1 H, CH).
13C NMR (CDCl3, 75 MHz): d = 14.2 (CH3), 22.3, 26.4, 27.6, 28.6,
32.4, 44.9 (CH2), 60.9 (OCH2), 96.9 (CH), 124.9, 142.8, 156.7,
163.7, 164.8 (C).
UV-Vis (MeCN, nm): lmax (log e) = 219 (3.65), 248 (3.74), 298
(3.96), 402 (3.45).
MS (EI, 70 eV): m/z (%) = 302 (M+ [35Cl], 13), 275 (210), 228 (7),
(2Z)-Ethyl 2-[3-Decyl-4-hydroxy-5-oxofuran-2(5H)-yl-
idene]acetate (5h)
1,3-Bis-silyl enol ether 4h (0.500 g, 1.21 mmol), (COCl)2 (0.184 g,
1.45 mmol), and TMSOTf (0.135 g, 0.60 mmol) in CH2Cl2 (30 mL)
gave 5h after chromatography (n-hexane–EtOAc, 5:1) as a yellow-
ish oil (0.166 g, 42%).
173 (16), 161 (25), 130 (64), 104 (76), 55 (100), 43 (80), 29 (90).
UV-Vis (MeCN, nm): lmax (log e) = 215 (3.76), 298 (4.01).
Anal. Calcd for C14H19ClO5 (302.751): C, 55.54; H, 6.33. Found: C,
54.91; H, 5.89.
IR (neat): 3445 (br), 2927 (m), 1793 (w), 1644 (s), 1135 (m) cm–1.
Acknowledgment
1H NMR (CDCl3, 300 MHz): d = 0.88 (t, J = 6.7 Hz, 3 H, CH3),
1.28 (m, 14 H, 7 × CH2), 1.33 (t, J = 7.1 Hz, 3 H, CH3), 1.58 (m, 2
H, CH2), 2.34 (t, J = 7.5 Hz, 2 H, CH2), 4.27 (q, J = 7.1 Hz, 2 H,
OCH2), 5.41 (s, 1 H, CH).
13C NMR (CDCl3, 75 MHz): d = 14.1, 14.2 (CH3), 22.5, 22.7, 27.8,
29.2, 29.3, 29.4 (CH2), 29.5 (2 × CH2), 31.9 (CH2), 60.9 (OCH2),
97.1 (CH), 125.4, 142.5, 156.8, 163.7, 164.9 (C).
MS (EI, 70 eV): m/z (%) = 324 (M+, 21), 279 (24), 250 (24), 212
(37), 198 (20), 151 (36), 130 (82), 70 (43), 57 (48), 43 (100), 29
(67).
Financial support from the Ministry of Education of Vietnam (scho-
larship to V.T.H.N.), from the DAAD (scholarship to E.B.), from
the state of Mecklenburg-Vorpommern (Landesforschungsschwer-
punkt ‘Neue Wirkstoffe und Screeningverfahren’), and from the
Deutsche Forschungsgemeinschaft is gratefully acknowledged.
References
(1) For a review of 1,3-bis-silyl enol ethers, see: Langer, P.
Synthesis 2002, 441.
(2) (a) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980,
102, 3534. (b) Simoneau, B.; Brassard, P. Tetrahedron
1986, 14, 3767. (c) Molander, G. A.; Cameron, K. O. J. Am.
Chem. Soc. 1993, 115, 830.
(3) (a) Langer, P.; Stoll, M. Angew. Chem. Int. Ed. 1999, 38,
1803; Angew. Chem. 1999, 111, 1919. (b) Langer, P.;
Schneider, T.; Stoll, M. Chem. Eur. J. 2000, 6, 3204.
(c) Langer, P.; Eckardt, T.; Schneider, T.; Göbel, C.; Herbst-
Irmer, R. J. Org. Chem. 2001, 66, 2222. (d) Langer, P.;
Eckardt, T.; Stoll, M.; Karimé, I.; Müller, P.; Saleh, N. N. R.
Eur. J. Org. Chem. 2001, 3657. (e) Ahmed, Z.; Langer, P. J.
Org. Chem. 2004, 69, 3753. (f) Bose, G.; Langer, P. Synlett
2005, 1021. (g) Ahmed, Z.; Langer, P. Tetrahedron 2005,
61, 2055.
UV-Vis (MeCN, nm): lmax (log e) = 218 (3.76), 248 (3.83), 299
(4.06), 401 (3.61).
Anal. Calcd for C18H28O5 (324.412): C, 66.64; H, 8.70. Found: C,
66.54; H, 9.00.
(2Z)-Ethyl 2-[3-(3-Chloropropyl)-4-hydroxy-5-oxofuran-2-
(5H)-ylidene]acetate (7a)
Compound 6a (1.05 g, 3.00 mmol), (COCl)2 (0.457 g, 3.60 mmol),
and TMSOTf (0.333 g, 1.50 mmol) in CH2Cl2 (60 mL) gave 7a after
chromatography (n-hexane–EtOAc, 5:1) as a yellowish solid (0.573
g, 73%).
IR (KBr): 3099 (br), 2987 (s), 1787 (s), 1655 (s), 1397 (s), 1308 (s),
1163 (m), 1108 (m), 1040 (s), 707 (w) cm–1.
(4) Desage-El Murr, M.; Nowaczyk, S.; Le Gall, T.;
Mioskowski, C.; Amekraz, B.; Moulin, C. Angew. Chem.
Int. Ed. 2003, 42, 1289; Angew. Chem. 2003, 115, 1327.
(5) (a) Holker, J. S.; O’Brien, E.; Moore, R. N.; Vederas, J. C. J.
Chem. Soc., Chem. Commun. 1983, 192. (b) Holker, J. S.;
Kaneda, M.; Ramer, S. E.; Vederas, J. C. J. Chem. Soc.,
Chem. Commun. 1987, 1099.
1H NMR (CDCl3, 300 MHz): d = 1.31 (t, J = 7.1 Hz, 3 H, CH3),
2.12 (m, J = 6.5 Hz, 2 H, CH2), 2.58 (t, J = 7.2 Hz, 2 H, CH2), 3.59
(t, J = 6.2 Hz, 2 H, CH2Cl), 4.28 (q, J = 7.1 Hz, 2 H, OCH2), 5.48
(s, 1 H, CH).
13C NMR (CDCl3, 75 MHz): d = 14.2 (CH3), 29.8, 30.1, 43.9 (CH2),
60.9 (OCH2), 97.6 (CH), 123.2, 142.9, 156.1, 163.2, 163.3 (C).
MS (EI, 70 eV): m/z (%) = 262 (M+ [37Cl], 5), 260 (M+ [35Cl], 33),
232 (18), 214 (47), 169 (43), 145 (48), 127 (28), 108 (20), 70 (78),
55 (53), 41 (55), 29 (100).
(6) Langer, P.; Bellur, E. J. Org. Chem. 2003, 68, 9742.
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V. T. H. Nguyen et al.
PAPER
(10) Katritzky, A. R.; Wang, Z.; Wang, M.; Wilkerson, C. R.;
Hall, C. D.; Akhmedov, N. G. J. Org. Chem. 2004, 69, 6617.
(11) Sekiyama, Y.; Fujimoto, Y.; Hasumi, K.; Endo, A. J. Org.
Chem. 2001, 66, 5649.
(12) (a) Sato, T.; Itoh, T.; Fujisawa, T. Chem. Lett. 1982, 1559.
(b) Liang, J. C.; Cross, J. O. Mol. Cryst. Liq. Cryst. 1986,
132, 123.
(13) (a) Matsuo, K.; Kitaguchi, I.; Takata, Y.; Tanaka, K. Chem.
Pharm. Bull. 1980, 28, 2494. (b) Doleschall, G.; Seres, P.;
Kovacs, A. J. Chem. Res., Miniprint 1991, 2, 324.
(14) Augelli-Szafran, C. E.; Blankley, C. J.; Roth, B. D.; Trivedi,
B. K.; Bousley, R. F. J. Med. Chem. 1993, 36, 2943.
(7) (a) Bose, G.; Nguyen, V. T. H.; Ullah, E.; Lahiri, S.; Görls,
H.; Langer, P. J. Org. Chem. 2004, 69, 9128. (b) Bellur, E.;
Görls, H.; Langer, P. Eur. J. Org. Chem. 2005, 2074.
(c) Nguyen, V. T. H.; Langer, P. Tetrahedron Lett. 2005, 46,
815. (d) Nguyen, V. T. H.; Bellur, E.; Appel, B.; Langer, P.
Synthesis 2006, 1103.
(8) (a) Clemo, N. G.; Gedge, D. R.; Pattenden, G. J. Chem. Soc.,
Perkin Trans. 1 1981, 1448. (b) Gill, G. B.; James, G. D.;
Gates, K. V.; Pattenden, G. J. Chem. Soc., Perkin Trans. 1
1993, 2567.
(9) Huckin, S. N.; Weiler, L. Can. J. Chem. 1974, 52, 1343.
Synthesis 2006, No. 17, 2865–2872 © Thieme Stuttgart · New York